Bicyclo proline

Other potent peptide mimetic NS3 protease inhibitors have been reported that incorporate a serine trap on the C-terminal end of the peptide. Thus, the inhibitory activity of telaprevir (VX-950, 59), (7nM vs. NS3, 300 nM vs. the la replicon) is based on truncation of the polypeptide substrate, maximizing binding by alteration of amino acids at the scissile site, and capping both N- and C-terminal ends, the latter with a known dicarbonyl serine trap. This compound has exhibited impressive antiviral activity in animals, and showed a 4.4 log drop in viral load in genotype 1-infected patients in a Phase lb clinical trial [110]. Telaprevir is expected to enter Phase 3 clinical trials in 2007. Additional bicyclo-proline-based P2 tetrapeptides, represented by analog 60 (Kj = 22 nM), have been explored. Although the compounds are selective inhibitors of NS3, little or no cell-based replicon activity was reported, presumably due to poor cellular permeability [111-114], A diastereomer of telaprevir, has been reported to inhibit the replicon with an EC50 of 0.55 pM [115]. 

The asymmetric [3 + 4] cycloaddition is readily achieved using chiral auxiliaries or catalysts [16]. The efficiency of the chiral auxiliary approach is illustrated in the [3-1-4] cycloaddition with cyclopentadiene. The vinyldiazoacetate 6, with (T)-pantolactone as the chiral auxiliary, generated the bicyclo[3.2.1]octadiene 75 in 87% yield and 76% dia-stereomeric excess (Eq. 10) [82]. Alternatively, the chiral rhodium prolinate Rh2(S-DOSP)4-catalyzed reaction of 4 generated the bicyclo[3.2.1]octadiene 76 in 77% yield and with 93% enantiomeric excess (Eq. 11) [83]. 

The authors reported the chiral separation of proline and thereonine amino acid up to 20 and 6g, respectively, in a single run. Micropreparative resolution of lecucine was presented. The resolution was discussed with respect to the degree of sorbent saturation with copper(II), elution rate, eluent concentration, temperature, and column loading condition [16]. Weinstein [74] reported the micropreparative separation of alkylated amino acids on a Chiral ProCu column. In another article, a preparative chiral resolution of 3-methylene-7-benzylidene-bicyclo[3.3.1]nonane was achieved on 7.5% silver(I)-d-camphor- 10-sulfonate CSP [75]. Later, Shieh et al. [71] used L-proline-loaded silica gel for the chiral resolution of (ft,5 )-phcnylcthanolaminc as the Schiff base of 2-hydroxy-4-methoxyacetophenone. Gris et al. [76] presented the preparative separations of amino acids on Chirosolve L-proline and Chirosolve L-pipecolic acid CSPs. 

Microwave irradiation of a mixture of cyclohexenones and ethyl acetoacetate adsorbed on the surface of solid lithium 5-(2)-prolinate leads to the stereoselective construction of bicyclo[2.2.2]octanone (69) systems through Michael addition and subsequent intramolecular aldolization (Ranu et al., 2000). Electron-rich aromatic compounds react with formaldehyde and a secondary amine under solvent-free condition and microwave irradiation in a microwave oven to produce amino ethylated products (70) in good to excellent yields (Mojtahedi et al., 2000). 

Hexenyl radicals cyclize to cyclopentylmethyl radicals (see Volume 4, Chapter 4.2). Thus radical decarboxylation of 6-heptenoic acids, by whatever means, usually results in die formation of five-mem-v beied rings. Although this fact had been appreciated previously it is only recendy, widi the advent of the 0-acyl thiohydroxamates, that it has been exploited from a syndietic point of view. An example is provided by the synthesis of bicyclo[4.3.0]proline derivatives from aspartic acid carried out by the Barton group (equation 51). It will be noted that activation of die C—C double bond acting as a radical trap is not necessary in these intramolecular reactions. 

A simple route to a bicyclo[2.2.2]octanone system was achieved by Michael reaction under microwave irradiation of a mixture of cyclohexenones and ethyl acetoacetate adsorbed on the surface of solid lithium (5)-( )-prolinate followed by intramolecular aldolization on a column of basic Al2O3 5 (Scheme 5.31). The bicyclo[2.2.2]octane system is the core unit of several biologically active natural products and a useful intermediate for synthetic manipulation. ... 

Fig. 11.6 Structures of bridged bicyclic proline mimetics (22) 2-aza-bicyclo[2.2.1]hep-tane-3-carboxylic acid, (23) 2-aza-bicy-clo[2.2.1]hept-5-ene-3-carboxylic acid, (24) 7-aza-bicyclo[2.2.1]heptane-l-carboxylic acid, (25) 2-aza-bicyclo[2.2.1]hexane-l carboxylic acid, (26) 2-aza-bicyclo[2.2.1]hexane-...

In another example, rhodium carboxylates, chirally modified with mandelate or proline-derived compounds, were used in intramolecular cyclopropanation of unsaturated diazo ketones (e.g., 4) to give bicyclo[3.1.0]hexanonc products in 97% yield with 12% ee7f>. 

Methyl (lB.,4R,5R)-Bicyclo[2.2.t]hept-2-ene-4-carboxylate and Benzyl (S)-Prolinate Hydrochloride ... 

Over 120 references to this heterocyclic ring system has appeared since Mosby1 reviewed the literature and found 28 references prior to 1957. The octahydro derivatives, in addition to being called 1,4-diaza-bicyclo 4.3.0)nonanes or 1,2-trimethylenepiperazines, are also known as anhydrides or lactams of proline with a second amino acid or as diketo-piperazines. The disproportionately large number of octahydro derivatives of this ring system will be treated separately in Section IV,D. 

Chlor-propyl)-2,4-dioxo-5-methyl-imidazolidin bildet durch intramolekulare N-Al-kylierung (vgl. S. 521) 2,4-Dioxo-5-methyl-l,3-diaza-bicyclo[3.3.0]octan, das sich zu 2-Methyl-DL-prolin hydrolysieren laBt. Die benotigte Vorstufe erhalt man durch Bucherer-Reaktion (s.S. 538) mit l-Hydroxy-4-oxo-pentan5 ... 

Iwabuchi with coworkers designed a series of 4-silylo)yproline derivatives with a view to confer lipophilic properties to the proline motif and thereby secure a basis for the catalytic activity growth. They found that (2S,4R)- and (2R,4R)-4-silylo yprolines 30 or their BU4N salts 31 (Figure 10.3) exhibit enhanced catalytic potencies to enantioselectively convert a-sym-metric keto-aldehyde 36 to bicyclo[3.3.1]-type products 37 or ent-37 with opposite enantiopreferences and different enantiocontrolling proficiencies (Scheme 10.8). Unexpectedly, the use of carbojylate (2S,4R)-31 (5 mol%) markedly enhanced the aldolisation rate to complete the reaction in 3 h at room temperature and furnish 77% 37 with 98% diastereomeric excess and... 

Organocatalytic asymmetric reaction between 1,4-cyclohexanedione and nitroalkenes afford bicyclo-[3.2.1]octane derivatives containing four contiguous stereogenic centers (Scheme 6.41). The product formation involves a domino Michael-Henry process using a proline-based bifunctional catalyst. The reaction gives good selectivity and yield in THF, and 4-nitrobenzoic acid is the most effective additive for this transformation [46]. 

Pro line tetrazole catalysts (category C in Figure 1.1) are readily accessible from L-proline (1) [158]. They are remarkably useful in asymmetric synthesis [159]. As shown in Figure 1.2, the pfCj of tetrazole is very similar to that of carboxyUc acid. Moreover, the advantage of tetrazole catalysts is their robust and lipophihc nature compared to L-proline (1) itself, which allows them to escape parasitic bicyclo-oxazolidinone formation [160]. 

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